Skip to main content
Erschienen in: Journal of Cancer Research and Clinical Oncology 1/2009

01.01.2009 | Original Paper

Differential IL-4/Stat6 activities correlate with differential expression of regulatory genes SOCS-1, SHP-1, and PP2A in colon cancer cells

verfasst von: Qin Yuan, Pin Dong Li, Ben Hui Li, Xian Zi Yang, Shuang Bing Xu, Xiao Hong Liu, Fu Xiang Zhou, Wen Jie Zhang

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 1/2009

Einloggen, um Zugang zu erhalten

Abstract

Purpose

To investigate potential differences in the expression of Stat6 regulatory genes that may influence IL-4/Stat6 activities (phenotypes) in colon cancer cells.

Methods

RT-PCR method was employed to examine the constitutive mRNA expression of Stat6 negative regulators SOCS-1 and SHP-1, and positive regulator PP2A in colon cancer cell lines HT-29 and Caco-2. Stat6 protein expression and nuclear phosphorylation were detected using Western blotting.

Results

Caco-2 cells carrying inactive Stat6null phenotype showed normal constitutive expression of Stat6 but decreased phosphorylation of nuclear Stat6 compared with HT-29 cells carrying active Stat6high phenotype. Stat6null Caco-2 cells expressed increased levels of mRNA and protein of SOCS-1 and SHP-1, and decreased mRNA expression of PPP2CA and PPP2CB, encoding two critical subunits of PP2A.

Conclusions

Constitutively increased expression of Stat6 negative regulators SOCS-1 and SHP-1, together with decreased expression of positive regulator PP2A, may play a role in forming the inactive Stat6null phenotype in colon cancer cells.
Literatur
Zurück zum Zitat Ansel KM, Djuretic I, Tanasa B, Rao A (2006) Regulation of Th2 differentiation and IL-4 locus accessibility. Annu Rev Immunol 24:607–656PubMedCrossRef Ansel KM, Djuretic I, Tanasa B, Rao A (2006) Regulation of Th2 differentiation and IL-4 locus accessibility. Annu Rev Immunol 24:607–656PubMedCrossRef
Zurück zum Zitat Bromberg J (2002) Stat proteins and oncogenesis. J Clin Invest 109:1139–1142PubMed Bromberg J (2002) Stat proteins and oncogenesis. J Clin Invest 109:1139–1142PubMed
Zurück zum Zitat Bruns HA, Kaplan MH (2006) The role of constitutively active Stat6 in leukemia and lymphoma. Crit Rev Oncol Hematol 57(3):245–253PubMedCrossRef Bruns HA, Kaplan MH (2006) The role of constitutively active Stat6 in leukemia and lymphoma. Crit Rev Oncol Hematol 57(3):245–253PubMedCrossRef
Zurück zum Zitat Dickensheets H, Vazquez N, Sheikh F et al (2007) Suppressor of cytokine signaling-1 is an IL-4-inducible gene in macrophages and feedback inhibits IL-4 signaling. Genes Immun 8:21–27PubMedCrossRef Dickensheets H, Vazquez N, Sheikh F et al (2007) Suppressor of cytokine signaling-1 is an IL-4-inducible gene in macrophages and feedback inhibits IL-4 signaling. Genes Immun 8:21–27PubMedCrossRef
Zurück zum Zitat Galka E, Thompson JL, Zhang WJ, Poritz LS, Koltun WA (2004) Stat6 (null phenotype) human lymphocytes exhibit increased apoptosis. J Surg Res 122:14–20PubMedCrossRef Galka E, Thompson JL, Zhang WJ, Poritz LS, Koltun WA (2004) Stat6 (null phenotype) human lymphocytes exhibit increased apoptosis. J Surg Res 122:14–20PubMedCrossRef
Zurück zum Zitat Hanson EM, Dickensheets H, Qu CK, Donnelly RP, Keegan AD (2003) Regulation of the dephosphorylation of Stat6. Participation of Tyr-713 in the interleukin-4 receptor alpha, the tyrosine phosphatase SHP-1, and the proteasome. J Biol Chem 278:3903–3911PubMedCrossRef Hanson EM, Dickensheets H, Qu CK, Donnelly RP, Keegan AD (2003) Regulation of the dephosphorylation of Stat6. Participation of Tyr-713 in the interleukin-4 receptor alpha, the tyrosine phosphatase SHP-1, and the proteasome. J Biol Chem 278:3903–3911PubMedCrossRef
Zurück zum Zitat Haque SJ, Harbor P, Tabrizi M, Yi T, Williams BR (1998) Protein-tyrosine phosphatase Shp-1 is a negative regulator of IL-4- and IL-13-dependent signal transduction. J Biol Chem 273:33893–33896PubMedCrossRef Haque SJ, Harbor P, Tabrizi M, Yi T, Williams BR (1998) Protein-tyrosine phosphatase Shp-1 is a negative regulator of IL-4- and IL-13-dependent signal transduction. J Biol Chem 273:33893–33896PubMedCrossRef
Zurück zum Zitat Haque SJ, Harbor PC, Williams BR (2000) Identification of critical residues required for suppressor of cytokine signaling-specific regulation of interleukin-4 signaling. J Biol Chem 275:26500–26506PubMedCrossRef Haque SJ, Harbor PC, Williams BR (2000) Identification of critical residues required for suppressor of cytokine signaling-specific regulation of interleukin-4 signaling. J Biol Chem 275:26500–26506PubMedCrossRef
Zurück zum Zitat Hebenstreit D, Horejs-Hoeck J, Duschl A (2005) JAK/STAT-dependent gene regulation by cytokines. Drug News Perspect 18:243–249PubMedCrossRef Hebenstreit D, Horejs-Hoeck J, Duschl A (2005) JAK/STAT-dependent gene regulation by cytokines. Drug News Perspect 18:243–249PubMedCrossRef
Zurück zum Zitat Hebenstreit D, Wirnsberger G, Horejs-Hoeck J, Duschl A (2006) Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine Growth Factor Rev 3:173–188CrossRef Hebenstreit D, Wirnsberger G, Horejs-Hoeck J, Duschl A (2006) Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine Growth Factor Rev 3:173–188CrossRef
Zurück zum Zitat Kacha AK, Fallarino F, Markiewicz MA, Gajewski TF (2000) Cutting edge: spontaneous rejection of poorly immunogenic P1.HTR tumors by Stat6-deficient mice. J Immunol 165:6024–6028PubMed Kacha AK, Fallarino F, Markiewicz MA, Gajewski TF (2000) Cutting edge: spontaneous rejection of poorly immunogenic P1.HTR tumors by Stat6-deficient mice. J Immunol 165:6024–6028PubMed
Zurück zum Zitat Lechward K, Awotunde OS, Swiatek W, Muszynska G (2001) Protein phosphatase 2A: variety of forms and diversity of functions. Acta Biochem Pol 48:921–933 Lechward K, Awotunde OS, Swiatek W, Muszynska G (2001) Protein phosphatase 2A: variety of forms and diversity of functions. Acta Biochem Pol 48:921–933
Zurück zum Zitat Levings MK, Schrader JW (1999) IL-4 inhibits the production of TNF-alpha and IL-12 by STAT6-dependent and–independent mechanisms. J Immunol 162:5224–5229PubMed Levings MK, Schrader JW (1999) IL-4 inhibits the production of TNF-alpha and IL-12 by STAT6-dependent and–independent mechanisms. J Immunol 162:5224–5229PubMed
Zurück zum Zitat Li BH, Yang XZ, Li PD et al (2008) IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells. Biochem Biophys Res Commun 369:554–560PubMedCrossRef Li BH, Yang XZ, Li PD et al (2008) IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells. Biochem Biophys Res Commun 369:554–560PubMedCrossRef
Zurück zum Zitat Losman J, Chen XP, Jiang H et al (1999) IL-4 signaling is regulated through the recruitment of phosphatases, kinases, and SOCS proteins to the receptor complex. Cold Spring Harb Symp Quant Biol 64:405–416PubMedCrossRef Losman J, Chen XP, Jiang H et al (1999) IL-4 signaling is regulated through the recruitment of phosphatases, kinases, and SOCS proteins to the receptor complex. Cold Spring Harb Symp Quant Biol 64:405–416PubMedCrossRef
Zurück zum Zitat Martens N, Uzan G, Wery M, Hooghe R, Hooghe-Peters EL, Gertler A (2005) Suppressor of cytokine signaling 7 inhibits prolactin, growth hormone, and leptin signaling by interacting with STAT5 or STAT3 and attenuating their nuclear translocation. J Biol Chem 280:13817–13823PubMedCrossRef Martens N, Uzan G, Wery M, Hooghe R, Hooghe-Peters EL, Gertler A (2005) Suppressor of cytokine signaling 7 inhibits prolactin, growth hormone, and leptin signaling by interacting with STAT5 or STAT3 and attenuating their nuclear translocation. J Biol Chem 280:13817–13823PubMedCrossRef
Zurück zum Zitat Matsumoto A, Seki Y, Kubo M et al (1999) Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice. Mol Cell Biol 19:6396–6407PubMed Matsumoto A, Seki Y, Kubo M et al (1999) Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice. Mol Cell Biol 19:6396–6407PubMed
Zurück zum Zitat Mitsuyasu H, Izuhara K, Mao XQ, Gao PS, Arinobu Y (1998) Ile50Val variant of IL4R alpha upregulates IgE synthesis and associates with atopic asthma. Nat Genet 19:119–121PubMedCrossRef Mitsuyasu H, Izuhara K, Mao XQ, Gao PS, Arinobu Y (1998) Ile50Val variant of IL4R alpha upregulates IgE synthesis and associates with atopic asthma. Nat Genet 19:119–121PubMedCrossRef
Zurück zum Zitat Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE (1999) The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 17:701–738PubMedCrossRef Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE (1999) The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 17:701–738PubMedCrossRef
Zurück zum Zitat Ostrand-Rosenberg S, Grusby MJ, Clements VK (2000) Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J Immunol 165:6015–6019PubMed Ostrand-Rosenberg S, Grusby MJ, Clements VK (2000) Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J Immunol 165:6015–6019PubMed
Zurück zum Zitat Ostrand-Rosenberg S, Sinha P, Clements V et al (2004) Signal transducer and activator of transcription 6 (Stat6) and CD1: inhibitors of immunosurveillance against primary tumors and metastatic disease. Cancer Immunol Immunother 53:86–91PubMedCrossRef Ostrand-Rosenberg S, Sinha P, Clements V et al (2004) Signal transducer and activator of transcription 6 (Stat6) and CD1: inhibitors of immunosurveillance against primary tumors and metastatic disease. Cancer Immunol Immunother 53:86–91PubMedCrossRef
Zurück zum Zitat Pang YH, Zhen CQ, Yang XZ, Zhang WJ (2007) Increased expression and activation of IL-12-induced Stat4 in the mucosa of ulcerative colitis patients. Cell Immunol 248:115–120PubMedCrossRef Pang YH, Zhen CQ, Yang XZ, Zhang WJ (2007) Increased expression and activation of IL-12-induced Stat4 in the mucosa of ulcerative colitis patients. Cell Immunol 248:115–120PubMedCrossRef
Zurück zum Zitat Ram PA, Waxman DJ (1999) SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J Biol Chem 274:35553–35561PubMedCrossRef Ram PA, Waxman DJ (1999) SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J Biol Chem 274:35553–35561PubMedCrossRef
Zurück zum Zitat Rane SG, Reddy EP (2002) JAKs, STATs and Src kinases in hematopoiesis. Oncogene 21:3334–3358PubMedCrossRef Rane SG, Reddy EP (2002) JAKs, STATs and Src kinases in hematopoiesis. Oncogene 21:3334–3358PubMedCrossRef
Zurück zum Zitat Shimoda K, van Deursen J, Sangster MY et al (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380:630–633PubMedCrossRef Shimoda K, van Deursen J, Sangster MY et al (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380:630–633PubMedCrossRef
Zurück zum Zitat Shirakawa I, Deichmann KA, Izuhara I, Mao I, Adra CN, Hopkin JM (2000) Atopy and asthma: genetic variant of IL-4 and IL-13 signalling. Immunol Today 21:60–64PubMedCrossRef Shirakawa I, Deichmann KA, Izuhara I, Mao I, Adra CN, Hopkin JM (2000) Atopy and asthma: genetic variant of IL-4 and IL-13 signalling. Immunol Today 21:60–64PubMedCrossRef
Zurück zum Zitat Takeda K, Kamanaka M, Tanaka T, Kishimoto T, Akira S (1996) Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. J Immunol 157:3220–3222PubMed Takeda K, Kamanaka M, Tanaka T, Kishimoto T, Akira S (1996) Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. J Immunol 157:3220–3222PubMed
Zurück zum Zitat Thierfelder WE, van Deursen JM, Yamamoto K et al (1996) Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382:171–174PubMedCrossRef Thierfelder WE, van Deursen JM, Yamamoto K et al (1996) Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382:171–174PubMedCrossRef
Zurück zum Zitat Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O’Shea JJ (2004) Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev 202:139–156PubMedCrossRef Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O’Shea JJ (2004) Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev 202:139–156PubMedCrossRef
Zurück zum Zitat Woetmann A, Brockdorff J, Lovato P et al (2003) Protein phosphatase 2A (PP2A) regulates interleukin-4-mediated STAT6 signaling. J Biol Chem 278:2787–2791PubMedCrossRef Woetmann A, Brockdorff J, Lovato P et al (2003) Protein phosphatase 2A (PP2A) regulates interleukin-4-mediated STAT6 signaling. J Biol Chem 278:2787–2791PubMedCrossRef
Zurück zum Zitat Wurster AL, Tanaka T, Grusby MJ (2000) The biology of Stat4 and Stat6. Oncogene 19:2577–2584PubMedCrossRef Wurster AL, Tanaka T, Grusby MJ (2000) The biology of Stat4 and Stat6. Oncogene 19:2577–2584PubMedCrossRef
Zurück zum Zitat Yoshimura A (2005) Negative regulation of cytokine signaling. Clin Rev Allergy Immunol 28:205–220PubMedCrossRef Yoshimura A (2005) Negative regulation of cytokine signaling. Clin Rev Allergy Immunol 28:205–220PubMedCrossRef
Zurück zum Zitat Zhang WJ, Degli-Esposti MA, Cobain TJ, Cameron PU, Christiansen FT, Dawkins RL (1990) Differences in gene copy number carried by different MHC ancestral haplotypes: quantitation after physical separation of haplotypes by pulsed field gel electrophoresis. J Exp Med 1:2101–2114CrossRef Zhang WJ, Degli-Esposti MA, Cobain TJ, Cameron PU, Christiansen FT, Dawkins RL (1990) Differences in gene copy number carried by different MHC ancestral haplotypes: quantitation after physical separation of haplotypes by pulsed field gel electrophoresis. J Exp Med 1:2101–2114CrossRef
Zurück zum Zitat Zhang WJ, Koltun WA, Tilberg AF, Thompson JL, Chorney MJ (2003) Genetic control of Interleukin-4-induced activation of the human signal transducer and activator 6 signaling pathway. Hum Immunol 64:402–415PubMedCrossRef Zhang WJ, Koltun WA, Tilberg AF, Thompson JL, Chorney MJ (2003) Genetic control of Interleukin-4-induced activation of the human signal transducer and activator 6 signaling pathway. Hum Immunol 64:402–415PubMedCrossRef
Zurück zum Zitat Zhang WJ, Koltun WA, Thompson JL et al (2004) Human B lymphoblast cell lines defective of Stat6 signaling produce high levels of proinflammatory cytokines IL-12, TNF-α and IFN-γ. Int J Oncol 24:447–453PubMed Zhang WJ, Koltun WA, Thompson JL et al (2004) Human B lymphoblast cell lines defective of Stat6 signaling produce high levels of proinflammatory cytokines IL-12, TNF-α and IFN-γ. Int J Oncol 24:447–453PubMed
Zurück zum Zitat Zhang MS, Zhou YF, Xie CH et al (2006) STAT6 specific shRNA inhibits proliferation and induces apoptosis in colon cancer HT-29 cells. Cancer Lett 243:38–46PubMedCrossRef Zhang MS, Zhou YF, Xie CH et al (2006) STAT6 specific shRNA inhibits proliferation and induces apoptosis in colon cancer HT-29 cells. Cancer Lett 243:38–46PubMedCrossRef
Zurück zum Zitat Zhang WJ, Li BH, Yang XZ et al (2008) IL-4-induced Stat6 activities affect apoptosis and gene expression in breast cancer cells. Cytokine 42:39–47PubMedCrossRef Zhang WJ, Li BH, Yang XZ et al (2008) IL-4-induced Stat6 activities affect apoptosis and gene expression in breast cancer cells. Cytokine 42:39–47PubMedCrossRef
Metadaten
Titel
Differential IL-4/Stat6 activities correlate with differential expression of regulatory genes SOCS-1, SHP-1, and PP2A in colon cancer cells
verfasst von
Qin Yuan
Pin Dong Li
Ben Hui Li
Xian Zi Yang
Shuang Bing Xu
Xiao Hong Liu
Fu Xiang Zhou
Wen Jie Zhang
Publikationsdatum
01.01.2009
Verlag
Springer-Verlag
Erschienen in
Journal of Cancer Research and Clinical Oncology / Ausgabe 1/2009
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-008-0429-8

Weitere Artikel der Ausgabe 1/2009

Journal of Cancer Research and Clinical Oncology 1/2009 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.